FGF1 Protein May Be Contender for T2D Therapy

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Fibroblast growth factor 1 (FGF1) of the FGF family of proteins, was found to be transcriptionally regulated by PPARc in adipose tissue, and FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet.

In this study, recombinant FGF1 (rFGF1) resulted in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycemia.

A single injection of the protein FGF1 stabilized glucose levels in diabetic mice without inducing the side effects associated with current diabetes treatment, making it a potential therapy for insulin resistance and type 2 diabetes, researchers reported.

The effects were sustained even with repeat injections, which reversed insulin insensitivity without inducing hypoglycemia, explained Jae Myoung Suh, PhD, of the Salk Institute for Biological Studies in La Jolla, Calif., and colleagues.

Even at high doses, treatment with recombinant fibroblast growth factor 1 (rFGF1) did not cause glucose to drop to dangerously low levels or trigger weight gain, bone loss, heart failure, or liver stenosis, they said in a research letter in Nature.

The mechanism responsible for FGF1's glucose stabilizing effect is not yet understood, but Suh and colleagues showed this action to be independent of its growth stimulating effect, making it a potential target for a novel diabetes treatment.

The researchers said they hope to move on to human clinical trials within the next few years.

"Type 2 diabetes occurs when the body does not respond to insulin anymore," Suh told MedPage Today. "We were able to correct the fundamental defect that leads to type 2 diabetes, and that is the goal the research and medical field is striving for."

High-Fat Diets and Diabetic Mice

FGF1 is an autocrine/paracrine regulator that binds to heparin sulphate proteoglycans, which inhibits its circulation. The growth factor is known to be involved in various physiological processes, including embryonic development, vessel development, and tumor growth.

The discovery of a phenotype for the FGF1 knockout mouse established the PPAR-gamma-FGF1 (PPARG-FGF1) axis as critical for maintaining metabolic homeostasis and insulin sensitization.

Downes said the finding came as a big surprise.

"The FGF1 protein in mouse models had been knocked out for a number of years, but basically no one had found any kind of phenotype before this," he told MedPage Today. "Growth effects had been seen in cell culture, but in vivo there had been nothing."

Their earlier work and the work of others led the researchers to investigate whether endocrinization of the non-endocrine FGF1 elicited glucose-lowering effects.

A Single rFGF1 Injection

When they injected rFGF1 into genetically induced (ob/ob and db/db) and diet-induced (DIO) insulin-resistant mice, they found that a single injection of 0.5 mg kg-1 rFGF1 was sufficient to normalize glucose levels in severely hyperglycemic ob/ob mice.

Maximal glucose lowering was achieved within 18 to 24 hours, and sustained effects were seen for more than 48 hours. The effect was found to be dose dependent, but even at the maximal dose (2.0mg kg-1) treatment did not result in hypoglycemia.

Potent glucose lowering was also seen in both db/db and DIO mouse models, and the mode of delivery (intravenous or intraperitoneal) did not effect outcomes.

Treatment with rFGF1 was also found to have no effect on blood glucose or insulin levels in nondiabetic, chow-fed mice.

The researchers observed a transient suppression of food intake that correlated with a temporary decrease in body weight, but injection of rFGF1 similarly reduced glucose levels under fasting conditions, dissociating the glucose-lowering effects of rFGF1 from its effect on food intake.

FGF1 Unique Among FGF Receptors

FGF1 is considered the universal ligand for FGF receptors (FGFRs) in its ability to bind and activate each of the alternatively spliced forms of the four tyrosine kinase FGF receptors (FGFR1-FGFR4), whereas other members of the FGF superfamily demonstrate receptor specificity.

"To determine whether other autocrine/paracrine FGFs have similar blood glucose lowering activity when given pharmacologically, we tested a selection of FGFs with specificities covering all seven FGFR receptors," the researchers wrote. "FGF1 seems unique in its ability to lower blood glucose: FGF2, FGF9, and FGF10 failed to do so. Furthermore, recombinant human FGF1 (hFGF1) was similarly able to normalize blood glucose in diabetic mice, suggesting an evolutionarily conserved pathway."

When the researchers subjected ob/ob mice to serial injections with 0.5 mg kg-1 of rFGF1 every other day for 35 days (chronic treatment), the glucose lowering was sustained with minimal changes in body weight or composition.

A similar glucose-lowering effect was seen in pair-fed ob/ob mice, indicating that the transient reduction in food intake after chronic treatment with rFGF1 did not account for the beneficial glucose-lowering effects

The fasting blood glucose levels of chronically rFGF1-treated ob/ob mice were 50% lower than in control mice, and remained lower throughout the glucose tolerance test (GTT) with a coincident decrease in insulin levels. Furthermore, rFGF1-treated mice showed a marked improvement in insulin sensitivity as measured by an insulin tolerance test (ITT).

Although there was no significant effect on free fatty acids, cholesterol, and triglyceride levels in serum, chronic treatment with rFGF1 decreased hepatic steatosis and increased liver glycogen content. No significant changes were detected in serum metabolic hormone levels.

"Furthermore, chronic treatment with rFGF1 of DIO mice, a strain that more closely models the majority of human type 2 diabetes, also resulted in pronounced and sustained lowering of blood glucose levels as well as in increased insulin sensitization as measured by GTT and ITT," the researchers wrote, adding that "these beneficial effects in DIO mice were observed without significant changes in body weight, organ weights, and feeding trends."

Truncated FGF1 Also Normalized Glucose

Since rFGF1 is a prototype of a growth factor family, the researchers recognized its potential for inducing unwanted cell proliferation, and they sought to determine whether the mitogen properties of rFGF1 could be dissociated from its glucose-lowering activities.

They did this by generating an FGF1 ligand that lacked the first 24 residues from the amino terminus.

The truncation was predicted to have significant effects on the binding affinity of FGF1 for all FGFRs, and while it did show a marked decrease in binding affinity for FGFRs compared with the native ligand, it was still able to bind FGF1c and FGFR2c.

The ligand "also retained the feeding suppression effects observed with rFGF1," the researchers wrote. "The synthetic effects of exogenous rFGF1 on physiology, such as glucose homeostasis and the feeding behavior therefore differ from, and are independent of, its classical role as a growth factor and mitogen."

More Study Needed

Suh and colleagues said that their findings identify "a neomorphic insulin-sensitizing action for FGF1 in which systemic delivery of the normally autocrine/paracrine FGF1 through parenteral routes results in potent and sustained correction of hyperglycemia and insulin sensitization.

"Our findings indicate that the metabolic effects of exogenous FGF1 are mediated through FGFr1 in adipose tissue; however, additional studies will be necessary to exclude the involvement of additional receptors and/or tissues in the body-side effects attributed to parenterally delivered rFGF1," they wrote.

They concluded that "we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes."

The authors disclosed no relevant relationships with industry.

Several co-authors disclosed receiving grants from the National Institutes of Health, the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, Ipsen/Biomeasure, the California Institute for Regenerative Medicine, The Ellison Medical Foundation, the National Health and Medical Research Council, the European Research Council, the Human Frontier Science Program, the Netherlands Organisation for Scientific Research, the Dutch Digestive Foundation, the Dutch Diabetes Foundation, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Dental and Craniofacial Research, and the National Institute of Diabetes and Digestive and Kidney Diseases.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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